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3. Independent Tissue-Based Biomarkers in Endometrioid Endometrial Cancer: Tumor Budding in Microsatellite Instability and WHO Grading in Copy-Number-Low Patients.

Author

Stögbauer, Fabian, Geß, Barbara, Brambs, Christine, Lautizi, Manuela, Kacprowski, Tim, Ourailidis, Iordanis, Bronger, Holger, Kiechle, Marion, Noske, Aurelia, Keller, Gisela, Jesinghaus, Moritz, Poremba, Christopher, Weichert, Wilko, and Boxberg, Melanie

Subjects
PATIENT aftercare, STATISTICS, MULTIVARIATE analysis, MANN Whitney U Test, FISHER exact test, ENDOMETRIAL tumors, RESEARCH funding, DESCRIPTIVE statistics, KAPLAN-Meier estimator, TUMOR markers, DATA analysis software, DATA analysis, HEALTH planning, PROPORTIONAL hazards models
Abstract

Simple Summary: Rrisk assessment of microsatellite instability (MSI) and copy-number (CN)-low endometrial adenocarcinomas constitutes a major challenge. We aimed to identify tissue-based morphologic biomarkers that might help in the prognostic stratification, comprehensively analyzing one finding cohort (TCGA-UCEC) and two independent validation cohorts. Histomorphologic parameters (WHO grading, tumor budding (TB), tumor–stroma ratio, tumor-infiltrating lymphocytes (TIL), "microcystic, elongated, fragmented" (MELF) pattern) were analyzed. For each quantitative parameter, a two-tiered system was developed utilizing systematically determined cutoffs. In MSI tumors, TB (≥3 buds/high-power field) was detected to be an independent prognostic factor for inferior outcomes and lymph node metastases. The finding was confirmed in two validation cohorts. For CN-low tumors, solely WHO grading was independently prognostic with inferior outcomes for high-grade tumors. Therefore, we propose the utilization of TB and WHO-based grading, two tissue-based and easy-to-assess biomarkers, in MSI/CN-low endometrial carcinomas for improved clinical management. The molecular characterization of endometrial endometrioid adenocarcinomas has provided major advances in its prognostic stratification. However, risk assessment of microsatellite instability (MSI) and copy-number (CN)-low cases remains a challenge. Thus, we aimed to identify tissue-based morphologic biomarkers that might help in the prognostic stratification of these cases. Histomorphologic parameters (WHO grading, tumor budding (TB), tumor–stroma ratio (as a quantitative description of stromal desmoplasia), tumor-infiltrating lymphocytes (TIL), "microcystic, elongated, fragmented" (MELF) pattern) were analyzed in resection specimens of the TCGA-UCEC cohort (n = 228). For each quantitative parameter, a two-tiered system was developed utilizing systematically determined cutoffs. Associations with survival outcomes were calculated in univariate and multivariate analysis and validated in two independent cohorts. In MSI tumors, only TB remained an independent prognostic factor. TB (≥3 buds/high-power field) was associated with inferior outcomes and with lymph node metastases. The prognostic significance of TB was confirmed in two validation cohorts. For CN-low tumors, established grading defined by the WHO was independently prognostic with inferior outcomes for high-grade tumors. The evaluation of TB might help in identifying MSI-patients with unfavorable prognosis who, e.g., could benefit from lymphadenectomy. WHO-based grading facilitates independent prognostic stratification of CN-low endometrioid adenocarcinomas. Therefore, we propose the utilization of TB and WHO-based grading, two tissue-based and easy-to-assess biomarkers, in MSI/CN-low endometrial carcinomas for improved clinical management. [ABSTRACT FROM AUTHOR]

Published
2023
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4. The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis

Author

Gunther, Claudia, He, Gui-Wei, Kremer, Andreas E., Murphy, James M., Petrie, Emma J., Amann, Kerstin, Vandenabeele, Peter, Linkermann, Andreas, Poremba, Christopher, Schleicher, Ulrike, Dewitz, Christin, Krautwald, Stefan, Neurath, Markus F., Becker, Christoph, and Wirtz, Stefan

Subjects
Inflammation -- Analysis, Hepatoma -- Risk factors, Necrosis -- Analysis, Health care industry
Abstract

Although necrosis and necroinflammation are central features of many liver diseases, the role of programmed necrosis in the context of inflammation-dependent hepatocellular death remains to be fully determined. Here, we have demonstrated that the pseudokinase mixed lineage kinase domain-like protein (MLKL), which plays a key role in the execution of receptor-interacting protein (RIP) kinase-dependent necroptosis, is upregulated and activated in human autoimmune hepatitis and in a murine model of inflammation-dependent hepatitis. Using genetic and pharmacologic approaches, we determined that hepatocellular necrosis in experimental hepatitis is driven by an MLKL-dependent pathway that occurs independently of RIPK3. Moreover, we have provided evidence that the cytotoxic activity of the proinflammatory cytokine IFN-γ in hepatic inflammation is strongly connected to induction of MLKL expression via activation of the transcription factor STAT1. In summary, our results reveal a pathway for MLKL-dependent programmed necrosis that is executed in the absence of RIPK3 and potentially drives the pathogenesis of severe liver diseases., Introduction Although the liver is an organ of remarkable regenerative capacity, cell death-related compensatory tissue injury responses commonly culminate in fibrosis and eventually cirrhosis, a major cause of morbidity worldwide. [...]

Published
2016
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10. Clinical molecular imaging in intestinal graft-versus-host disease: mapping of disease activity, prediction, and monitoring of treatment efficiency by positron emission tomography

Author

Stelljes, Matthias, Hermann, Sven, Albring, Jörn, Köhler, Gabriele, Löffler, Markus, Franzius, Christiane, Poremba, Christopher, Schlösser, Verena, Volkmann, Sarah, Opitz, Corinna, Bremer, Christoph, Kucharzik, Torsten, Silling, Gerda, Schober, Otmar, Berdel, Wolfgang E., Schäfers, Michael, and Kienast, Joachim

Published
2008
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30. Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Author

Engel, Christoph, Forberg, Jochen, Holinski-Feder, Elke, Pagenstecher, Constanze, Plaschke, Jens, Kloor, Matthias, Poremba, Christopher, Pox, Christian P., Rüschoff, Josef, Keller, Gisela, Dietmaier, Wolfgang, Rümmele, Petra, Friedrichs, Nicolaus, Mangold, Elisabeth, Buettner, Reinhard, Schackert, Hans K., Kienle, Peter, Stemmler, Susanne, Moeslein, Gabriela, and Loeffler, Markus

Published
2006
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35. Graft-versus-host disease after allogeneic hematopoietic stem cell transplantation induces a CD8+ T cell-mediated graft-versus-tumor effect that is independent of the recognition of alloantigenic tumor targets

Author

Stelljes, Matthias, Strothotte, Robert, Pauels, Hans-Gerd, Poremba, Christopher, Milse, Michaela, Specht, Christiane, Albring, Jörn, Bisping, Guido, Scheffold, Christian, Kammertoens, Thomas, Oelmann, Elisabeth, Silling, Gerda, Berdel, Wolfgang E., and Kienast, Joachim

Published
2004
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44. Leiomyosarcoma of the inferior vena cava: Radical surgery and vascular reconstruction

Author

Knoefel Wolfram T, Poremba Christopher, Raffel Andreas, Rehders Alexander, Alexander Andrea, and Eisenberger Claus F

Subjects
Surgery, RD1-811, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Vascular leiomyosarcoma are rare tumors typically originating from the inferior vena cava (IVC). Due to nonspecific clinical signs most tumors are diagnosed at advanced stages. Complete surgical resection remains the only potential curative therapeutic option. Surgical strategy is particularly influenced by the level of the IVC affected. Due to the topographic relation to the renal veins level-II involvement of the IVC raises special surgical challenges with respect to the maintenance of venous outflow. Case presentation We herein report two cases of leiomyosarcoma of the IVC with successful en bloc resection and individualized caval reconstruction. One patient presented with a large intramural and intraluminal mass and received a complete circumferential resection. Reconstruction was performed by graft replacement of the caval segment affected. The other patient displayed a predominantly extraluminal tumor growth and underwent semicircumferential resection of the IVC including the confluence of the left renal vein. In this case vascular reconstruction was performed by cavoplasty and reinsertion of the left renal vein into the proximal portion of the IVC. Resection margins of both patients were tumor free and no clinical signs of venous insufficiency of the lower extremity occurred. Conclusion This paper presents two cases of successfully managed leiomyosarcomas of the vena cava and exemplifies two different options for vascular reconstruction in level II sarcomas and includes a thorough review of the literature.

Published
2009
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46. Constitutive Activation of Neuregulin/ERBB3 Signaling Pathway in Clear Cell Sarcoma of Soft Tissue1

Author

Schaefer, Karl-Ludwig, Brachwitz, Kristin, Braun, Yvonne, Diallo, Raihanatou, Wai, Daniel H., Zahn, Susanne, Schneider, Dominik T, Kuhnen, Cornelius, Vollmann, Arabel, Brockhoff, Gero, Gabbert, Helmut E., and Poremba, Christopher

Subjects
Receptor, ErbB-3, Neuregulin-1, Oligonucleotides, Nucleic Acid Hybridization, Soft Tissue Neoplasms, Gene Expression Regulation, Neoplastic, Kinetics, Pyrimidines, Cell Line, Tumor, mental disorders, Humans, Sarcoma, Clear Cell, Phosphorylation, Alleles, Research Article, Oligonucleotide Array Sequence Analysis, Signal Transduction
Abstract

Clear cell sarcoma of soft tissue (CCSST) represents a highly malignant tumor of the musculoskeletal system that is characterized by the chromosomal translocation t(12;22)(q13;q12) of the Ewing sarcoma gene (EWSR1) and activating transcription factor 1 (ATF1). In a former microarray expression study, we identified ERBB3, a member of the epidermal growth factor receptor (EGFR) family, as a promising new diagnostic marker in the differential diagnosis of CCSST. Here we show that, besides ErbB3, all CCSST cell lines (n = 8) also express the ErbB2 receptor or the ErbB4 receptor, representing an adequate coreceptor of ErbB3. The phosphorylation status of ErbB3 revealed these receptor pairs to be either constitutively activated in CCSST cells with high neuregulin-1 (NRG1) expression (n = 4) or activatable by exogenic NRG1 in cells showing low amounts of NRG1 mRNA (n = 4). Exogenous NRG1 stimulated the growth of a subset of CCSST cells but did not affect the kinetics of another subset. This difference was not strictly dependent on endogenous NRG1 expression; however, the growth-inhibiting effect of the pan-ErbB tyrosine kinase inhibitor CI-1033 or PD158780 clearly correlated with NRG1 expression indicating an autocrine growth stimulation loop, which may constitute an interesting target of new therapeutic strategies in this tumor entity.

Published
2006

49. Molecular characterization of commonly used cell lines for bone tumor research: A trans-European EuroBoNet effort.

Author

Ottaviano, Laura, Schaefer, Karl-Ludwig, Gajewski, Melanie, Huckenbeck, Wolfgang, Baldus, Stefan, Rogel, Uwe, Mackintosh, Carlos, de Alava, Enrique, Myklebost, Ola, Kresse, Stine H., Meza-Zepeda, Leonardo A., Serra, Massimo, Cleton-Jansen, Anne-Marie, Hogendoorn, Pancras C. W., Buerger, Horst, Aigner, Thomas, Gabbert, Helmut E., and Poremba, Christopher

Published
2010
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50. Primary peripheral primitive neuroectodermal tumor/Ewing's tumor of the testis in a 46-year-old man—differential diagnosis and review of the literature.

Author

Heikaus, Sebastian, Schaefer, Karl-Ludwig, Eucker, Jan, Hogrebe, Esther, Danebrock, Raihanatou, Wai, Daniel H., Krenn, Veit, Gabbert, Helmut E., and Poremba, Christopher

Subjects
PERIPHERAL nerve tumors, EWING'S sarcoma, TESTIS tumors, MIDDLE-aged men, CANCER in men, DIFFERENTIAL diagnosis, LITERATURE reviews, MEDICAL literature, DISEASES
Abstract

Summary: Peripheral primitive neuroectodermal tumor/Ewing''s tumors are rare bone and soft tissue malignancies with a highly aggressive clinical course and early metastases occurring at multiple peripheral sites. Here, we present for the first time a case of a 46-year-old man with a primary peripheral primitive neuroectodermal tumor/Ewing''s tumor of the testis. The diagnosis of peripheral primitive neuroectodermal tumor/Ewing''s tumor was established by histology, immunohistochemistry, and molecular pathology. The tumor revealed a rapid progress in 2 months'' time. Therefore, the patient was included in the EURO-E.W.I.N.G.99 study and was placed on chemotherapy. However, the tumor progressed during ongoing therapy, and the patient died in March 2008. In conclusion, though being reported here for the first time, peripheral primitive neuroectodermal tumor/Ewing''s tumors should be considered in the differential diagnosis of blue round cell tumors of the testis. A rapid and correct diagnosis of this entity is crucial for fast and accurate therapy, which is stressed by the fatal case presented here. [Copyright &y& Elsevier]

Published
2009
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